HEMOPHILIA

Hemophilia

Pathogenesis and Clinical Manifestations

Hemophilia is an X-linked recessive hemorrhagic disease due to mutations in the F8 gene (hemophilia A or classic hemophilia) or F9 gene (hemophilia B). The disease affects 1 in 10,000 males worldwide, in all ethnic groups; hemophilia A represents 80% of all cases. Male subjects are clinically affected; women, who carry a single mutated gene, are generally asymptomatic. Family history of the disease is absent in approximately 30% of cases. In these cases, 80% of the mothers are carriers of the de novo mutated allele. More than 500 different mutations have been identified in the F8 or F9 genes. One of the most common hemophilia A mutations results from an inversion of the intron 22 sequence, which is present in 40% of cases of severe hemophilia A. Advances in molecular diagnosis now permit precise identification of mutations, allowing accurate diagnosis of women carriers of the hemophilia gene in affected families.

Clinically, hemophilia A and hemophilia B are indistinguishable. The disease phenotype correlates with the residual activity of FVIII or FIX and can be classified as severe (< 1%), moderate (1–5%), or mild (6–30%). In the severe and moderate forms, the disease is characterized by bleeding episodes into the joints (hemarthroses), soft tissues, and muscles after minor trauma or even spontaneously. Patients with mild disease experience infrequent bleeding that is usually secondary to trauma. Among those with residual FVIII or FIX activity >25% of normal, the disease is discovered only by bleeding after major trauma or during routine presurgery laboratory tests. Typically, the global tests of coagulation show only an isolated prolongation of the aPTT assay. Patients with hemophilia have normal bleeding times and platelet counts. The diagnosis is made after specific determination of FVIII or FIX clotting activity.

Early in life, bleeding may present after circumcision or rarely as intracranial hemorrhages. The disease is more evident when children begin to walk or crawl. In the severe form, the most common bleeding manifestations are the recurrent hemarthroses, which can affect every joint but mainly affect knees, elbows, ankles, shoulders, and hips. Acute hemarthroses are painful, and clinical signs are local swelling and erythema. To avoid pain, the patient may adopt a fixed position, which leads eventually to muscle contractures. Very young children unable to communicate verbally show irritability and a lack of movement of the affected joint. Chronic hemarthroses are debilitating, with synovial thickening and synovitis in response to the intraarticular blood. After a joint has been damaged, recurrent bleeding episodes result in the clinically recognized "target joint," which then establishes a vicious cycle of bleeding, resulting in progressive joint deformity that in critical cases requires surgery as the only therapeutic option. Hematomas into the muscle of distal parts of the limbs may lead to external compression of arteries, veins, or nerves, which can evolve to a compartment syndrome.

Bleeding into the oropharyngeal spaces, central nervous system, or the retroperitoneum is life-threatening and requires immediate therapy. Retroperitoneal hemorrhages can accumulate large quantities of blood along with formation of masses with calcification and inflammatory tissue reaction (pseudotumor syndrome), and they can also result in damage to the femoral nerve. Pseudotumors can also form in bones, especially long bones of the lower limbs. Hematuria is frequent among hemophilia patients, even in the absence of genitourinary pathology. It is often self-limited and may not require specific therapy.

Hemophilia: Treatment

Without treatment, patients with severe hemophilia have a limited life expectancy. Advances in the blood fractionation industry during World War II resulted in the realization that plasma could be used to treat hemophilia, but the volumes required to achieve even modest elevation of circulating factor levels limits the utility of plasma infusion as an approach to disease management. The discovery in the 1960s that cryoprecipitate fraction of plasma was enriched for FVIII, in addition to the eventual purification of FVIII and FIX from plasma, led to the introduction of home infusion therapy with factor concentrates in the 1970s. The availability of factor concentrates resulted in a dramatic improvement in life expectancy and in quality of life for people with severe hemophilia. However, the contamination of the blood supply with hepatitis viruses and, subsequently, HIV resulted in widespread transmission of these bloodborne infections within the hemophilia population; complications of HIV and of hepatitis C are now the leading causes of death among US adults with severe hemophilia. The introduction of viral inactivation steps in the preparation of plasma-derived products in the mid-1980s greatly reduced the risk of HIV and hepatitis, and the risks were further reduced by the successful production of recombinant FVIII and FIX proteins, both licensed in the 1990s. It is uncommon for hemophilic patients born after 1985 to have contracted either hepatitis or HIV, and for these individuals, life expectancy is in the range of 65 years of age.

Factor replacement therapy for hemophilia can be provided either in response to a bleeding episode or as a prophylactic treatment. Primary prophylaxis is defined as a strategy for maintaining the missing clotting factor at levels ~1% or higher on a regular basis in order to prevent bleeds, especially the onset of hemarthroses. Hemophilic boys receiving regular infusions of FVIII (3 days/week) or FIX (2 days/week) can reach puberty without detectable joint abnormalities. Although highly recommended, this regimen is performed for <30% of patients because of the high cost, difficulties in accessing peripheral veins in young patients, and the potential infectious and thrombotic risks of long-term central vein catheters.

General considerations regarding the treatment of bleeds in hemophilia include (1) the need to begin the treatment as soon as possible because symptoms often precede objective evidence of bleeding; because of the superior efficacy of early therapeutic intervention, classic symptoms of bleeding into the joint in a reliable patient, headaches, or automobile or other accidents, require prompt replacement and further laboratory investigation; and (2) the need to avoid drugs that hamper platelet function such as aspirin or aspirin-containing drugs; to control pain, drugs such as ibuprofen or propoxyphene are preferred.

Factor VIII and Factor IX are dosed in units. One unit is by definition the amount of FVIII (100 ng/mL) or FIX (5 g/mL) in 1 mL of normal plasma. One unit of FVIII per kilogram of body weight increases the plasma FVIII level by 2%. One can calculate the dose needed to increase FVIII levels to 100% in a 70-kg severe hemophilia patient (<1%) using the simple formula below. Thus, 3500 units of FVIII will raise the circulating level to 100%.

FVIII dose (IU) = Target FVIII levels – FVIII baseline levels x body weight (kg) x 0.5 unit/kg

The doses for FIX replacement are different from those for FVIII, because FIX recovery postinfusion is usually only 50% of the predicted value. Therefore, the formula for FIX replacement is

FIX dose (IU) = Target FIX levels – FIX baseline levels x body weight (kg) x 1.0 unit/kg

The FVIII half-life of 8–12 h requires injections twice a day to maintain therapeutic levels, whereas the FIX half-life is longer, ~24 h, so that once-a-day injection is sufficient. In specific situations such as postsurgery, continuous infusion of factor may be desirable because of its safety in achieving sustained factor levels at a lower total cost.

Cryoprecipitate is enriched with FVIII protein (each bag contains ~80 IU of FVIII) and was commonly used for the treatment of hemophilia A decades ago; it is still in use in some developing countries, but because of the risk of bloodborne diseases, this product should be avoided in hemophilia patients when factor concentrates are available.

Mild bleeds such as uncomplicated hemarthroses or superficial hematomas require initial therapy with factor levels of 30–50%. Additional doses to maintain levels of 15–25% for 2 or 3 days are indicated for severe hemarthroses, especially when these episodes affect the "target joint." Large hematomas, or bleeds into deep muscles, require factor levels of 50% or even higher if the clinical symptoms do not improve, and factor replacement may be required for a period of 1 week or longer. The control of serious bleeds, including those that affect the oropharyngeal spaces, central nervous system, and the retroperitoneum, require sustained protein levels of 50–100% for 7–10 days. Prophylactic replacement for surgery is aimed at achieving normal factor levels (100%) for a period of 7–10 days; replacement can then be tapered depending on the extent of the surgical wounds. Oral surgery is associated with extensive tissue damage, which usually requires factor replacement for 1–3 days coupled with oral antifibrinolytic drugs.

Non-Transfusion Therapy in Hemophilia

DDAVP (1-Deamino-8-D-Arginine Vasopressin)

DDAVP is a synthetic vasopressin analogue that causes a transient rise in FVIII and von Willebrand factor (vWF), but not FIX, through a mechanism involving release from endothelial cells. Patients with moderate or mild hemophilia A should be tested to determine if they respond to DDAVP before a therapeutic application. DDAVP at doses of 0.3 g/kg body weight infused over a 20-min period is expected to raise FVIII levels by two- to threefold over baseline, peaking between 30–60 min postinfusion. DDAVP does not improve FVIII levels in severe hemophilia A patients, as there are no stores to release. Repeated dosing of DDAVP results in tachyphylaxis because the mechanism is an increase in release rather than de novo synthesis of FVIII and vWF. More than three consecutive doses become ineffective and if further therapy is indicated, FVIII replacement is required to achieve hemostasis.

Antifibrinolytic Drugs

Bleeding in the gums, in the gastrointestinal tract, and during oral surgery requires the use of oral antifibrinolytic drugs such as -aminocaproic acid (EACA) or tranexamic acid to control local hemostasis. The duration of the treatment depending on the clinical indication is 1 week or longer. Tranexamic acid is given at doses of 25 mg/kg three to four times a day. EACA treatment requires a loading dose of 200 mg/kg (maximum of 10 g) followed by 100 mg/kg (maximum 30 g/d) every 6 h. These drugs are not indicated to control hematuria because of the risk of formation of an occlusive clot in the lumen of genitourinary tract structures.

Complications

Inhibitor Formation

The formation of alloantibodies to FVIII or FIX is currently the major complication of hemophilia treatment. The prevalence of inhibitors to FVIII is estimated at 5–10% of all cases and approximately 20% of severe hemophilia A patients. Inhibitors to FIX are detected in only 3–5% of all hemophilia B patients. The high-risk group for inhibitor formation includes severe deficiency (>80% of all cases of inhibitors), familial history of inhibitors, African descent, mutations in the FVIII or FIX gene resulting in deletion of large coding regions, or gross gene rearrangements. Inhibitors usually appear early in life, at a median of two years of age, and after 10 cumulative days of exposure.

The clinical diagnosis of inhibitor is suspected when patients do not respond to factor replacement at therapeutic doses. Inhibitors increase both morbidity and mortality in hemophilia. Because early detection of an inhibitor is critical to a successful correction of the bleeding or to eradication of the antibody, most hemophilia centers perform annual screening for inhibitors. The laboratory test required to confirm the presence of an inhibitor is an aPTT mixed with normal plasma. In most hemophilia patients, a 1:1 mix with normal plasma completely corrects the aPTT. In inhibitor patients, the aPTT on a 1:1 mix is abnormally prolonged, because the inhibitor neutralizes the FVIII clotting activity of the normal plasma. The Bethesda assay uses a similar principle and defines the specificity of the inhibitor and its titer. The results are expressed in Bethesda units (BU), in which 1 BU is the amount of antibody that neutralizes 50% of the FVIII or FIX present in normal plasma after 2 h of incubation at 37°C. Clinically, inhibitor patients are classified as low responders or high responders, which provides guidelines for optimal therapy. Therapy for inhibitor patients has two goals: the control of acute bleeding episodes and the eradication of the inhibitor. For the control of bleeding episodes, low responders, those with titers <5 BU, respond well to high doses of human or porcine FVIII (50–100 U/kg) with minimal or no increase in the inhibitor titers. However, high-responder patients—those with initial inhibitor titer >10 BU or an anamnestic response in the antibody titer to >10 BU even if low titer initially—do not respond to FVIII or FIX concentrates. The control of bleeding episodes in high-responder patients can be achieved by using concentrates enriched for prothrombin, FVII, FIX, FX [prothrombin complex concentrates (PCCs) or activated PCCs], and more recently by recombinant activated Factor VII (FVIIa) (Fig. 110-1). The rates of therapeutic success have been higher for FVIIa than for PCC or aPCC. For eradication of the inhibitory antibody, immunosuppression is not effective. The most effective strategy is immune tolerance induction (ITI) based on daily infusion of the missing protein until the inhibitor disappears, typically requiring periods longer than one year, with success rates in the range of 60%. Promising results have been obtained by adding anti-CD20 monoclonal antibody (rituximab) as a coadjuvant for the eradication of high levels of antibody in patients undergoing ITI.

Infectious Diseases

Hepatitis C virus (HCV) infection is the major cause of morbidity and the second leading cause of death in hemophilia patients exposed to older clotting factor concentrates. The vast majority of young patients treated with plasma-derived products from 1970 to 1985 became infected with HCV. It has been estimated that >80% of patients older than 20 years of age are HCV antibody positive as of 2006. The comorbidity of the underlying liver disease in hemophilia patients is clear when these individuals require invasive procedures; correction of both genetic and acquired (secondary to liver disease) deficiencies may be needed. Infection with HIV also swept the population of patients treated with plasma-derived concentrates two decades ago. Co-infection of HCV and HIV, present in almost 50% of hemophilia patients, is an aggravating factor for the evolution of liver disease. The response to HCV antiviral therapy in hemophilia is restricted to <30% of patients and is even poorer among those with both HCV and HIV infection. End-stage liver disease requiring organ transplantation may be curative for both the liver disease and for hemophilia.

Factor XI Deficiency

Factor XI is a zymogen of an active serine protease (FXIa) in the intrinsic pathway of blood coagulation that activates FIX (Fig. 110-1). There are two pathways for the formation of FXIa. In an aPTT-based assay, the protease is the result of activation by FXIIa in conjunction with high-molecular-weight kininogen and kallikrein. Thrombin appears to be the physiologic activator of FXI. The generation of thrombin by the tissue-factor/Factor VIIa pathway activates FXI on the platelet surface, which contributes to additional thrombin generation after the clot has formed and thus augments resistance to fibrinolysis through a thrombin-activated fibrinolytic inhibitor (TAFI).

Factor XI deficiency is a rare bleeding disorder that occurs in the general population at a frequency of one in a million. However, the disease is highly prevalent among Ashkenazi and Iraqi Jewish populations, reaching a frequency of 6% as heterozygotes and 0.1–0.3% as homozygotes. More than 65 mutations in the FXI gene have been reported, whereas two to three mutations are found among affected Jewish populations.

Normal FXI clotting activity levels range from 70 to 150 U/dL. In heterozygous patients with moderate deficiency, FXI ranges from 20 to 70 U/dL, whereas in homozygous or double heterozygote patients, FXI levels are <1–20 U/dL. Patients with FXI levels <10% of normal have a high risk of bleeding, but the disease phenotype does not always correlate with residual FXI clotting activity. A family history is indicative of the risk of bleeding in the propositus. Clinically, the presence of mucocutaneous hemorrhages such as bruises, gum bleeding, epistaxis, hematuria, and menorrhagia are common, especially following trauma. This hemorrhagic phenotype suggests that tissues rich in fibrinolytic activity are more susceptible to FXI deficiency. Postoperative bleeding is common but not always present, even among patients with very low FXI levels.

Factor XI Deficiency: Treatment

The treatment of FXI deficiency is based on the infusion of FFP at doses of 15–20 mL/kg to maintain trough levels ranging from 10 to 20%. Because FXI has a half-life of 40–70 h, the replacement therapy can be given on alternate days. The use of antifibrinolytic drugs is beneficial to control bleeds, with the exception of hematuria or bleeds in the bladder. The development of a FXI inhibitor was observed in 10% of severely FXI-deficient patients who received replacement therapy.

Other Rare Bleeding Disorders

Collectively, the inherited disorders resulting from deficiencies of clotting factors other than FVIII, FIX, and FXI (Table 110-1) represent a group of rare bleeding diseases. The bleeding symptoms in these patients vary from asymptomatic (dysfibrinogenemia or FVII deficiency) to life-threatening (FX or FXIII deficiency). There is no pathognomonic clinical manifestation that suggests one specific disease, but overall, in contrast to hemophilia, hemarthrosis is a rare event, and bleeding in the mucosal tract or after umbilical cord clamping is common. Individuals heterozygous for plasma coagulation deficiencies are often asymptomatic. The laboratory assessment for the specific deficient factor following screening with general coagulation tests (Table 110-1) will establish the diagnosis.

Replacement therapy using fresh frozen plasma (FFP) or PCCs (containing prothrombin, FVII, FIX and FX) provides adequate hemostasis in response to bleeds or as prophylactic treatment. The use of PCCs should be carefully monitored and avoided in patients with underlying liver disease or those at high risk for thrombosis because of the risk of DIC.

Familial Multiple Coagulation Deficiencies

Several bleeding disorders are characterized by the inherited deficiency of more than one plasma coagulation factor. To date, the genetic defects in two of these diseases have been characterized, and they provide new insights into the regulation of hemostasis by genes encoding proteins outside blood coagulation.

Combined Deficiency of Fv and Fvii

Patients with combined FV and FVIII deficiency exhibit ~5% of residual clotting activity of each factor. Interestingly, the disease phenotype is a mild bleeding tendency, often following trauma. An underlying mutation has been identified in the endoplasmic reticulum/Golgi intermediate compartment (ERGIC-53) gene, a mannose-binding protein localized in the Golgi apparatus that functions as a chaperone for both FV and FVIII. In other families, mutations in the multiple coagulation factor deficiency 2 (MCFD2) gene have been defined; this gene encodes a protein that forms a Ca2+-dependent complex with ERGIC-53 and provides cofactor activity in the intracellular mobilization of both FV and FVIII.


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